It has been shown that several amphipathic helical peptide mimetics of apolipoprotein (apo) A-l inhibit atherosclerosis, improve vascular function, and reduce inflammatory processes. It has also been shown that co-administration of peptide with statin regresses already-existing atherosclerotic lesions. We hypothesize that these peptides modify high density lipoprotein (HDL) or recruit phospholipids and apo A-l to form apo Al- containing particles which in turn recruit antiatherogenic enzymes such as paraoxonase-1 (PON-1) and/or platelet activating-factor acetylhydrolase (PAF-AH). We intend to determine if peptides have antiatherosclerotic properties in the absence of apo A-l or PON-1. We hypothesize that mimetic peptides act by recruiting apo A-l into new, more bioactive particles, or by modifying the structure of apo A-l so that it is more bioactive. This may allow it to recruit and/or activate PON-1, resulting in a reduction of atherogenic oxidized lipids. We will study three peptides: 4F, which is strongly atheroprotective; 3F[14], which has no observed atheroprotective properties; and peptide 2F, which is intermediate in its in vitro atheroprotective properties. These peptides differ only in the number of phenylalanine residues on the hydrophobic face. The following specific aims are proposed: Specific Aim 1: The role of apo A-l in peptide function. The hypothesis to be tested is that apo A-l is required for mimetic peptide function, a: We will study the effect of peptides on apo A-l synthesis and secretion, b: We will use atherosclerosis-susceptible mice, either expressing wild-type apo A-l or apo A-l null. We will study the requirement of apo A-l for peptide-mediated functions. Specific Aim 2: The role of PON-1 in peptide function. The hypothesis to be tested is that PON-1 is required for mimetic peptide function, a: Peptide-mediated changes in PON-1 levels and activity will be determined, b: Using atherosclerosis-susceptible mice expressing PON-1 or PON-1 null, anti-inflammatory properties of the peptides will be studied. HDL is considered to be protective against atherosclerotic heart disease. We are studying the major protein of HDL, apo A-l, using small molecules called peptides to mimic the properties of apo A-l. These studies will be done using mouse models that are susceptible to atherosclerosis. The objective is to better understand how apo A-l and HDL are protective, and to develop methods to improve those protective properties.